Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Receptor protein tyrosine kinases (PTKs) are cell surface transmembrane receptors which, upon binding of an extracellular ligand, triggers receptor dimerization and kinase activity. Signal transduction cascades initiated by PTK activation control a range of cellular processes including cell differentiation and apoptosis. One particular group of PTK receptors is the TAM family of receptors (Lai and Lemke, Neuron 6:691-704, 1991). Three members of this family have been identified to date designated Axl, Mer and Tyro3 (reviewed by Lemke and Rothlin, Nature Reviews (Immunology) 8:327-336, 2008). TAM receptor-mediated signaling is associated with tissue homeostasis in the nervous, reproductive and vascular systems. TAM signaling is also important in regulating innate immune systems including inhibiting the inflammatory response to pathogens and apoptotic cells by dendritic cells and macrophages and maturation of natural killer cells.
TAM receptors and their ligands crystallise as homo- and hetero-dimers. Each monomeric form of the receptor comprises an N-terminal region, a Gla-domain, a EGF-like domain, an immunoglobulin-like domain, a transmembrane domain and a PTK domain (Lemke and Rothlin, 2008 supra).
Demyelinating disease is a nervous system disorder in which the myelin sheath of neurons is damaged. This reduces signal transmission in affected nerves causing inter alia impairment of sensation, movement and cognition. Demyelinating disease encompasses multiple sclerosis (MS) and other idiopathic inflammatory demyelinating diseases. A proportion of patients which present with a first demyelinating event (FDE), also known as a clinically isolated syndrome (CIS) go onto develop MS. The early course of MS including the number of relapses in the first two years, is predictive of early development of permanent disease. One form of predictor of disease activity and the likelihood of progression from an FDE to MS is with an MRI (Brex et al., N. Engl. J. Med 346(3):158-164, 2002). The MRI detects lesions. Patients with no lesions have an 11% chance of MS and patients with two or more lesions have an 83-88% of MS, all within a 10 year period (Barkinof et al., Brain 120:2059-2069, 1997; O'Riorden et al., Brain 121:495-503, 1998). Whilst MRI is a useful tool, it is expensive and requires specialist equipment and training.
Oligodendrocytes are a major cell type damaged in these MS and other idiopathic inflammatory demyelinating diseases. Hence, the term “oligodendrocyte disease” is used to define demyelinating diseases which affect the oligodendrocytes and their ability to interact with various cell types in the demyelinating area. The TAM family of receptors has been found to be expressed in the nervous system including oligodendrocytes (Binder et al., The Journal of Neuroscience 28(2):5195-5206, 2008). Oligodendrocyte death is an early event in demyelinating disease (Barnett and Prineas, Ann. Neurol 55:459-468, 2004).
In accordance with the present disclosure, it has been determined that TAM receptors are a useful bio-indicator of demyelination and of oligodendrocyte survival and microglial modulation. The development of a molecular determinant of MS and other idiopathic inflammatory demyelinating disease enables early diagnosis and intervention and improve clinical outcomes for patients.